Regulation of Lipid and Lipoprotein Metabolism by Nuclear Receptors

核受体对脂质和脂蛋白代谢的调节

基本信息

批准号：
9195921
负责人：
Liya Yin
金额：
$ 39.04万
依托单位：
NORTHEAST OHIO MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9195921
关键词：
3&apos Untranslated Regions ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Adipose tissue Anti-Inflammatory Agents Anti-inflammatory Aorta Apolipoprotein A-I Apolipoprotein E Arterial Fatty Streak Atherosclerosis Cause of Death Cells Cholesterol Cholesterol Homeostasis Chronic Country Data Developed Countries Development Diabetes Mellitus Disease Employee Strikes Excretory function Fatty Liver Feces Foam Cells Gene Expression HNF4A gene Health Hepatic High Density Lipoproteins High Fat Diet Human Hyperlipidemia In Vitro Inflammation Inflammatory Inflammatory Response Intestines Knockout Mice LDL Cholesterol Lipoproteins Lead Lipids Lipoproteins Liver Liver diseases Messenger RNA Metabolic Metabolic stress Metabolism MicroRNAs Mus Nuclear Receptors Obesity Plant Roots Plasma Play Prevention RNA Binding Regulation Risk Factors Role Techniques Testing Tissues Untranslated RNA Untranslated Regions atherogenesis base disability fatty acid oxidation feeding hypolipidemia in vivo lipid metabolism macrophage non-alcoholic fatty liver novel overexpression prevent reverse cholesterol transport treatment strategy western diet

项目摘要

Project Summary Project Summary: Atherosclerotic cardiovascular diseases (CVD) are the most common causes of death and disability in the developed countries. Atherosclerosis is a chronic inflammatory disease, characterized by lipid accumulation in macrophages of arterial walls. ATP-binding cassette (ABC) transporters A1 (ABCA1) and G1 (ABCG1) are essential for preventing macrophages from developing into “foam” cells by promoting cholesterol efflux to lipid-free apoA-I or HDL, which subsequently delivers macrophage-derived cholesterol to the liver and intestinal lumen for excretion to the feces. Defective cholesterol efflux leads to formation of foam macrophages, which are activated to contribute to the inflammatory response during atherogenesis. MicroRNAs (miRNAs) are short, non-coding RNAs that bind to the 3'UTR of mRNAs to post-transcriptionally regulate gene expression. Recent studies have documented miRNAs as important regulators of lipid metabolism. We have generated miR-34aApoe double knockout (DKO) mice. Upon fed a Western diet, the DKO mice have a marked reduction in atherosclerotic lesions in both the aorta and aortic root as compared to Apoemice, which is accompanied by unchanged plasma LDL-C or HDL-C levels. Further studies show that miR-34a macrophages have a striking increase in Abca1 and Abcg1 expression and are protective against inflammatory response. Based on our preliminary studies, we hypothesize that inhibition of miR-34a protects against atherosclerosis by increasing macrophage reverse cholesterol transport and inhibiting inflammation. To test this hypothesis, we propose three specific aims to determine whether macrophage miR-34a regulates cholesterol efflux and reverse cholesterol transport, inflammation and atherosclerosis. We will use genetically modified mice and pharmacological manipulations together with state-of-the-art techniques to complete this project. Completion of the proposed studies may uncover a novel role of macrophage miR-34a in cholesterol metabolism, inflammation and atherosclerosis, and may also lead to identification of miR-34a as a novel target for prevention and/or regression of atherosclerosis.

项目概要项目摘要：动脉粥样硬化性心血管疾病 (CVD) 是导致死亡和死亡的最常见原因。动脉粥样硬化是一种以血脂为特征的慢性炎症性疾病。动脉壁巨噬细胞中 ATP 结合盒 (ABC) 转运蛋白 A1 (ABCA1) 和 G1 的积累。 (ABCG1) 对于通过促进胆固醇防止巨噬细胞发育成“泡沫”细胞至关重要流出为无脂 apoA-I 或 HDL，随后将巨噬细胞衍生的胆固醇输送至肝脏，排泄到粪便的肠腔有缺陷的胆固醇流出导致泡沫的形成。巨噬细胞，在动脉粥样硬化形成过程中被激活促进炎症反应。 MicroRNA (miRNA) 是短的非编码 RNA，可在转录后与 mRNA 的 3'UTR 结合最近的研究证明 miRNA 是脂质的重要调节因子。我们已经培育出 miR-34aApoe 双基因敲除 (DKO) 小鼠。与对照组相比，DKO 小鼠的主动脉和主动脉根部的动脉粥样硬化病变均显着减少。 Apoe--小鼠，其血浆 LDL-C 或 HDL-C 水平没有变化。 miR-34a巨噬细胞的 Abca1 和 Abcg1 表达显着增加，并且具有保护作用根据我们的初步研究，我们发现抑制 miR-34a 可以保护炎症反应。通过增加巨噬细胞逆转胆固醇转运和抑制炎症来对抗动脉粥样硬化。检验这一假设，我们提出了三个具体目标来确定巨噬细胞 miR-34a 是否调节胆固醇外流和逆转胆固醇运输、炎症和动脉粥样硬化我们将利用基因。改良小鼠和药理学操作以及最先进的技术来完成这一任务完成拟议的研究可能会揭示巨噬细胞 miR-34a 在胆固醇中的新作用。代谢、炎症和动脉粥样硬化，也可能导致 miR-34a 被鉴定为新靶点用于预防和/或消退动脉粥样硬化。